In this proposal we lay out a comprehensive research plan to evaluate our passive vaccination strategies targeting Staphylococcus aureus/MRSA to prevent or treat infections associated with S. aureus/MRSA. With the emergence of highly antibiotic-resistant bacterial strains, most notably MRSA, new approaches for combating bacterial infections are desperately needed. In this research proposal, Sorrento Therapeutics Inc. (STI) together with researchers from Montana State University have outlined experiments that will harness a powerful combination of chemistry, microbiology, and immunology to provide a solid rational basis for the development and evaluation of quorum quenching vaccines to prevent S. aureus infections. We will evaluate a passive vaccination strategy targeting the agr quorum sensing system of S. aureus for the protection against Staph infections, such as skin and soft tissue infections (SSTI), bacteremia, and mastitis caused by antibiotic-sensitive (MSSA) and -resistant Staphylococcus aureus (MRSA) strains. We will also establish active vaccination protocols that result in high quorum quenching antibody titers as the basis for our ultimate goal, the development of an effective S. aureus vaccine. The specific projects of our STTR research proposal are (1) Efficacy of passive anti-AIP immunotherapy for the prevention and therapy of Staphylococcus aureus infections. To establish the therapeutic efficacy of passive anti-AIP immunotherapy we will utilize anti-AIP1 and AIP3 murine monoclonal antibodies (mAbs) AP1-15B4 and AP3-29A2 and evaluate their efficacy in three S. aureus infection models in mice. These models will reflect common S. aureus infections in humans and animals, namely skin and soft tissue infection, systemic S. aureus infection, and mastitis. (2) Generation of AIP hapten-immunoconjugates and establishment of vaccination protocols. We will synthesize the original anti-AIP haptens AP1 and AP3. Furthermore, with the help of our collaborators, we have designed a new 2nd generation set of AIP haptens, namely more hydrolytically stable APTAM haptens that we will also synthesize. The haptens will be conjugated to a set of carrier proteins and the resulting immunoconjugates will be used for immunization studies in mice to establish active vaccination protocols. The successful completion of these two projects and the obtained data will be the basis for our Phase 2 proposal to design, evaluate, and develop an effective S. aureus vaccine for the human and veterinary markets. PUBLIC HEALTH RELEVANCE: Despite the approval of numerous antibiotics over the past 60 years, bacterial disease remains a serious public health problem. Many of the most harmful bacteria, including Staphylococcus aureus, develop resistance to approved antibiotics (so-called "superbugs") causing people with drug-resistant infections to become seriously ill or die. Sorrento Therapeutics Inc. is working on the development of a new way to prevent and even treat bacterial disease in a manner that we believe will be much more effective than using current antibiotic therapy and that will be unaffected by existing resistances.